ABSTRACT Chronic myelomonocytic leukemia (CMML) is a devastating cancer for which there is currently no effective therapy. Approximately 30% of CMML cases evolve to acute myelogenous leukemia AML soon after their initial diagnosis, contributing to the high morbidity and mortality (median survival: ~20 months). While recent sequencing efforts have identified numerous somatic mutations in CMML, little is known about the genetic predisposition of individuals to develop CMML. We recently reported an ASXL1/NRAS mutated CMML that occurred in an individual with a germline ANKRD26 variant familial thrombocytopenia syndrome, suggesting that previously unrecognized germline sequence variants (GSVs) may predispose patients to develop CMML and work cooperatively with somatic mutations (e.g. RAS pathway mutations) to promote disease progression (including transformation to AML). Consistent with this idea, we have identified two recurrent GSVs in the TCOF1 gene with much higher frequency in CMML patients than those in the normal population. Both GSVs change the nucleolar localization of wild-type TCOF1 protein and may partially inhibit WT TCOF1 function. Downregulating Tcof1 in vivo not only induced CMML-like phenotypes in a fraction of mice but also significantly shortened the survival of NrasQ61R/+ mice. Based on our preliminary data, we hypothesize that TCOF1 GSVs confer an increased risk for the development of CMML and genetically interact with somatic mutations (e.g. oncogenic RAS mutations and/or ASXL1 mutations) to drive CMML progression. We propose the following two specific aims to test our hypothesis: 1) To investigate whether TCOF1 GSVs confer an increased risk of CMML development and whether they associate with specific somatic mutations to promote CMML progression; 2) To establish leukemia cell lines and mouse model with targeted TCOF1 GSVs. Successful accomplishment of the proposed studies will not only provide fundamental perspectives on disease predisposition and genetic interactions between GSVs and somatic mutations, but also generate powerful tools for future mechanistic and translational research in the CMML field.